Citric Acid → N-((S)-1-(5-amino-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

HRID 2170388Notes

Reaction equation

HRID 2170388 reaction equation
OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:12]([C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[N:13][CH:14]=1.C(N(CC)C(C)C)(C)C.[F:51][CH:52]([F:68])[C:53]1[C:54]2[C@H:64]3[CH2:65][C@H:63]3[C:62]([F:67])([F:66])[C:55]=2[N:56]([CH2:58][C:59](O)=[O:60])[N:57]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(O)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:12]([C@@H:15]([NH:25][C:59](=[O:60])[CH2:58][N:56]2[C:55]3[C:62]([F:66])([F:67])[C@@H:63]4[CH2:65][C@@H:64]4[C:54]=3[C:53]([CH:52]([F:68])[F:51])=[N:57]2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[N:13][CH:14]=1

Participants

9

Reactant 6

HCID 311Citric AcidHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 902812892-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acidHCID 131732937(S)-N-(7-(5-amino-2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide TFA salt

Product 1

HCID 90281283N-((S)-1-(5-amino-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

Compound 49B (60 mg, 0.1 mmol) was dissolved in 1 mL of DMF and cooled to 0° C. To it was added N,N-diisopropylethylamine (0.09 mL, 0.5 mmol) followed by a solution of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (26 mg, 0.1 mmol) and HATU (56.5 mg, 0.15 mmol) in 1 mL of DMF. To it was added 0.5 mL of ethanol and 0.1 mL of 15% NaOH aqueous solution and stirred for 5 min. The reaction mixture was acidified with 5% citric acid and then extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ 8.23 (dd, 1H), 7.09 (q, 1H), 6.97 (d, 1H), 6.83-6.53 (m, 2H), 6.37 (m, 2H), 6.17 (d, 1H), 4.80-4.66 (m, 3H), 3.38 (s, 2H), 3.06 (dd, 1H), 2.97 (d, 4H), 2.91 (m, 1H), 2.55-2.42 (m, 2H), 1.44-1.34 (m, 1H), 1.12-1.00 (m, 1H). MS (m/z) 753.14 [M+H]+.

Workup

  1. extractionextracted with EtOAc
  2. customThe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by RP-HPLC
  7. washeluting with acetonitrile/H2O (with 0.1% TFA)

Sources & evidence

ORD record
ord-758ec330536446939f781825d4e91143
Source dataset
uspto-grants-2015_06
Patent number
US09050344B2

Reaction notes

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